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Apoptotic blebs from Leishmania major-infected macrophages as a new approach for cutaneous leishmaniasis vaccination (2020)
Journal Article
Faridnia, R., Kalani, H., Hezarjaribi, H. Z., Denny, P. W., Rafie, A., Fakhar, M., & Virgilio, S. (2020). Apoptotic blebs from Leishmania major-infected macrophages as a new approach for cutaneous leishmaniasis vaccination. Microbial Pathogenesis, 147, Article 104406. https://doi.org/10.1016/j.micpath.2020.104406

We focused on apoptotic blebs from Leishmania major-infected macrophages as a vaccine for cutaneous leishmaniasis. Apoptosis was induced in L. major-infected J774A.1 cells in order to prepare apoptotic blebs. Test groups of BALB/c mice were immunized... Read More about Apoptotic blebs from Leishmania major-infected macrophages as a new approach for cutaneous leishmaniasis vaccination.

An investigation of the antileishmanial properties of semi-synthetic saponins (2020)
Journal Article
Anderson, O., Beckett, J., Briggs, C., Natrass, L., Cranston, C., Wilkinson, E., …Denny, P. (2020). An investigation of the antileishmanial properties of semi-synthetic saponins. RSC Medicinal Chemistry, 11(7), 833-842. https://doi.org/10.1039/d0md00123f

Leishmaniasis is a neglected tropical disease caused by insect-vector borne protozoan parasites of the, Leishmania species. Whilst infection threatens and affects millions of the global poor, vaccines are absent and drug therapy limited. Extensive ef... Read More about An investigation of the antileishmanial properties of semi-synthetic saponins.

A BONCAT-iTRAQ method enables temporally resolved quantitative profiling of newly synthesised proteins in Leishmania mexicana parasites during starvation (2019)
Journal Article
Karunakaran, K., & Denny, P. W. (2019). A BONCAT-iTRAQ method enables temporally resolved quantitative profiling of newly synthesised proteins in Leishmania mexicana parasites during starvation. PLoS Neglected Tropical Diseases, 13(12), Article e0007651. https://doi.org/10.1371/journal.pntd.0007651

Adaptation to starvation is integral to the Leishmania life cycle. The parasite can survive prolonged periods of nutrient deprivation both in vitro and in vivo. The identification of parasite proteins synthesised during starvation is key to unravelli... Read More about A BONCAT-iTRAQ method enables temporally resolved quantitative profiling of newly synthesised proteins in Leishmania mexicana parasites during starvation.

Mining for natural product antileishmanials in a fungal extract library (2019)
Journal Article
Mbekeani, A., Jones, R., Bassas Llorens, M., Elliot, J., Regnault, C., Barrett, M., …Denny, P. (2019). Mining for natural product antileishmanials in a fungal extract library. International Journal for Parasitology: Drugs and Drug Resistance, 11, 118-128. https://doi.org/10.1016/j.ijpddr.2019.05.003

Leishmaniasis is a Neglected Tropical Disease caused by the insect-vector borne protozoan parasite, Leishmania species. Infection affects millions of the World's poorest, however vaccines are absent and drug therapy limited. Recently, public-private... Read More about Mining for natural product antileishmanials in a fungal extract library.

The identification of small molecule inhibitors of the plant inositol phosphorylceramide synthase which demonstrate herbicidal activity (2019)
Journal Article
Pinneh, E., Mina, J., Stark, M., Lindell, S., Luemmen, P., Knight, M., …Denny, P. (2019). The identification of small molecule inhibitors of the plant inositol phosphorylceramide synthase which demonstrate herbicidal activity. Scientific Reports, 9, Article 8083. https://doi.org/10.1038/s41598-019-44544-1

Resistance to 157 different herbicides and 88% of known sites of action has been observed, with many weeds resistant to two or more modes. Coupled with tighter environmental regulation, this demonstrates the need to identify new modes of action and n... Read More about The identification of small molecule inhibitors of the plant inositol phosphorylceramide synthase which demonstrate herbicidal activity.

Expression levels of inositol phosphorylceramide synthase modulate plant responses to biotic and abiotic stress in Arabidopsis thaliana (2019)
Journal Article
Pinneh, E., Stoppel, R., Knight, H., Knight, M., Steel, P., & Denny, P. (2019). Expression levels of inositol phosphorylceramide synthase modulate plant responses to biotic and abiotic stress in Arabidopsis thaliana. PLoS ONE, 14(5), Article e0217087. https://doi.org/10.1371/journal.pone.0217087

This research was undertaken to investigate the global role of the plant inositol phosphorylceramide synthase (IPCS), a non-mammalian enzyme previously shown to be associated with the pathogen response. RNA-Seq analyses demonstrated that over-express... Read More about Expression levels of inositol phosphorylceramide synthase modulate plant responses to biotic and abiotic stress in Arabidopsis thaliana.

Lytic reactions of drugs with lipid membranes (2018)
Journal Article
Britt, H. M., García-Herrero, C. A., Denny, P. W., Mosely, J. A., & Sanderson, J. M. (2019). Lytic reactions of drugs with lipid membranes. Chemical Science, 10(3), 674-680. https://doi.org/10.1039/c8sc04831b

Propranolol is shown to undergo lipidation reactions in three types of lipid membrane: (1) synthetic single-component glycerophospholipid liposomes; (2) liposomes formed from complex lipid mixtures extracted from E. coli or liver cells; and (3) in ce... Read More about Lytic reactions of drugs with lipid membranes.

Tamoxifen inhibits the biosynthesis of inositolphosphorylceramide in Leishmania (2018)
Journal Article
Trinconi, C. T., Miguel, D. C., Silber, A. M., Brown, C., Mina, J. G., Denny, P. W., …Uliana, S. R. (2018). Tamoxifen inhibits the biosynthesis of inositolphosphorylceramide in Leishmania. International Journal for Parasitology: Drugs and Drug Resistance, 8(3), 475-487. https://doi.org/10.1016/j.ijpddr.2018.10.007

Previous work from our group showed that tamoxifen, an oral drug that has been in use for the treatment of breast cancer for over 40 years, is active both in vitro and in vivo against several species of Leishmania, the etiological agent of leishmania... Read More about Tamoxifen inhibits the biosynthesis of inositolphosphorylceramide in Leishmania.

Yeast: bridging the gap between phenotypic and biochemical assays for high-throughput screening (2018)
Journal Article
Denny, P. W. (2018). Yeast: bridging the gap between phenotypic and biochemical assays for high-throughput screening. Expert Opinion on Drug Discovery, 13(12), 1153-1160. https://doi.org/10.1080/17460441.2018.1534826

Introduction: Both in vitro biochemical and phenotypic assay platforms have clear limitations in high throughput screening (HTS) for drug discovery. The use of genetically tractable model yeast as a vehicle for target-based HTS overcomes many of thes... Read More about Yeast: bridging the gap between phenotypic and biochemical assays for high-throughput screening.

Functional analyses of a putative, membrane-bound, peroxisomal import mechanism from the apicomplexan protozoan Toxoplasma gondii (2018)
Journal Article
Mbekeani, A., Stanley, W., Kalel, V., Dohan, N., Zalckvar, E., Scheiner, L., …Denny, P. (2018). Functional analyses of a putative, membrane-bound, peroxisomal import mechanism from the apicomplexan protozoan Toxoplasma gondii. Genes, 9(9), Article 434. https://doi.org/10.3390/genes9090434

Peroxisomes are central to eukaryotic metabolism, including the oxidation of fatty acids—which subsequently provide an important source of metabolic energy—and in the biosynthesis of cholesterol and plasmalogens. However, the presence and nature of p... Read More about Functional analyses of a putative, membrane-bound, peroxisomal import mechanism from the apicomplexan protozoan Toxoplasma gondii.

Identifying inhibitors of the Leishmania inositol phosphorylceramide synthase with antiprotozoal activity using a yeast-based assay and ultra-high throughput screening platform (2018)
Journal Article
Norcliffe, J., Mina, J., Alvarez-Ruiz, E., Cantizani-Perez, J., de Dios-Anton, F., Colmenarejo, G., …Denny, P. (2018). Identifying inhibitors of the Leishmania inositol phosphorylceramide synthase with antiprotozoal activity using a yeast-based assay and ultra-high throughput screening platform. Scientific Reports, 8, Article 3938. https://doi.org/10.1038/s41598-018-22063-9

Leishmaniasis is a Neglected Tropical Disease caused by the insect-vector borne protozoan parasite, Leishmania species. Infection affects millions of the world’s poorest, however vaccines are absent and drug therapy limited. Recently, public-private... Read More about Identifying inhibitors of the Leishmania inositol phosphorylceramide synthase with antiprotozoal activity using a yeast-based assay and ultra-high throughput screening platform.

A complex interplay between sphingolipid and sterol metabolism revealed by perturbations to the Leishmania metabolome caused by miltefosine (2018)
Journal Article
Armitage, E., Alqaisi, A., Godzien, J., Pena, I., Mbekeani, A., Alsonso-Herranz, V., …Barbas, C. (2018). A complex interplay between sphingolipid and sterol metabolism revealed by perturbations to the Leishmania metabolome caused by miltefosine. Antimicrobial Agents and Chemotherapy, 62(5), e02095-17. https://doi.org/10.1128/aac.02095-17

With the World Health Organization reporting over 30,000 deaths and 200-400,000 new cases annually, visceral Leishmaniasis is a serious disease affecting some of the world's poorest people. As drug resistance continues to rise, there is a huge unmet... Read More about A complex interplay between sphingolipid and sterol metabolism revealed by perturbations to the Leishmania metabolome caused by miltefosine.

Microbial protein targets: towards understanding and intervention (2017)
Journal Article
Denny, P. (2018). Microbial protein targets: towards understanding and intervention. Parasitology, 145(2), 111-115. https://doi.org/10.1017/s0031182017002037

The rise of antimicrobial resistance, coupled with a lack of industrial focus on antimicrobial discovery over preceding decades, has brought the world to a crisis point. With both human and animal health set to decline due to increased disease burden... Read More about Microbial protein targets: towards understanding and intervention.

Repurposing as a Strategy for the Discovery of New Anti-Leishmanials: The-State-of-the-Art (2017)
Journal Article
Charlton, R., Rossi-Bergmann, B., Denny, P. W., & Steel, P. G. (2018). Repurposing as a Strategy for the Discovery of New Anti-Leishmanials: The-State-of-the-Art. Parasitology, 145(2), 219-236. https://doi.org/10.1017/s0031182017000993

Leishmaniasis is a vector-borne neglected tropical disease caused by protozoan parasites of the genus Leishmania for which there is a paucity of effective viable non-toxic drugs. There are 1·3 million new cases each year causing considerable socio-ec... Read More about Repurposing as a Strategy for the Discovery of New Anti-Leishmanials: The-State-of-the-Art.

Everybody needs sphingolipids, right! Mining for new drug targets in protozoan sphingolipid biosynthesis (2017)
Journal Article
Mina, J., & Denny, P. (2018). Everybody needs sphingolipids, right! Mining for new drug targets in protozoan sphingolipid biosynthesis. Parasitology, 145(2), 134-147. https://doi.org/10.1017/s0031182017001081

Sphingolipids (SLs) are an integral part of all eukaryotic cellular membranes. In addition, they have indispensable functions as signalling molecules controlling a myriad of cellular events. Disruption of either the de novo synthesis or the degradati... Read More about Everybody needs sphingolipids, right! Mining for new drug targets in protozoan sphingolipid biosynthesis.

Functional and phylogenetic evidence of a bacterial origin for the first enzyme in sphingolipid biosynthesis in a phylum of eukaryotic protozoan parasites (2017)
Journal Article
Mina, J., Thye, J., Alqaisi, A., Bird, L., Dods, R., Groftehauge, M., …Denny, P. W. (2017). Functional and phylogenetic evidence of a bacterial origin for the first enzyme in sphingolipid biosynthesis in a phylum of eukaryotic protozoan parasites. Journal of Biological Chemistry, 292(29), 12208-12219. https://doi.org/10.1074/jbc.m117.792374

Toxoplasma gondii is an obligate, intracellular eukaryotic apicomplexan protozoan parasite that can cause fetal damage and abortion in both animals and humans. Sphingolipids are essential and ubiquitous components of eukaryotic membranes that are bot... Read More about Functional and phylogenetic evidence of a bacterial origin for the first enzyme in sphingolipid biosynthesis in a phylum of eukaryotic protozoan parasites.

The antifungal Aureobasidin A and an analogue are active against the protozoan parasite Toxoplasma gondii but do not inhibit sphingolipid biosynthesis (2017)
Journal Article
Alqaisi, A., Mbekeani, A., Bassas Llorens, M., Elhammer, A., & Denny, P. (2018). The antifungal Aureobasidin A and an analogue are active against the protozoan parasite Toxoplasma gondii but do not inhibit sphingolipid biosynthesis. Parasitology, 145(2), 148-155. https://doi.org/10.1017/s0031182017000506

Toxoplasma gondii is an obligate intracellular protozoan parasite of the phylum Apicomplexa, and toxoplasmosis is an important disease of both humans and economically important animals. With a limited array of drugs available there is a need to ident... Read More about The antifungal Aureobasidin A and an analogue are active against the protozoan parasite Toxoplasma gondii but do not inhibit sphingolipid biosynthesis.

An Efficient Method for the Synthesis of Peptoids with Mixed Lysine-type/Arginine-type Monomers and Evaluation of Their Anti-leishmanial Activity (2016)
Journal Article
Bolt, H., Denny, P., & Cobb, S. (2016). An Efficient Method for the Synthesis of Peptoids with Mixed Lysine-type/Arginine-type Monomers and Evaluation of Their Anti-leishmanial Activity. Journal of Visualized Experiments, 117, Article e54750. https://doi.org/10.3791/54750

This protocol describes the manual solid-phase synthesis of linear peptoids that contain two differently functionalized cationic monomers. In this procedure amino functionalized 'lysine' and guanido functionalized 'arginine' peptoid monomers can be i... Read More about An Efficient Method for the Synthesis of Peptoids with Mixed Lysine-type/Arginine-type Monomers and Evaluation of Their Anti-leishmanial Activity.